The long term objective of my laboratory is to understand the cellular and molecular mechanisms that underly tumor invasiveness in human gliomas. We have focused on the role of several proteases, their inhibitors and receptors (uPA) that appears to have a direct relationship with the invasive behavior of primary brain tumors, particularly glioblastoma. Recent data has suggested the presence of much higher levels of MMP-9 in glioblastoma samples compared to low- grade gliomas. In the next five years, we plan to focus on the molecular modulation of the expression of these MMP-9 as a basis for the molecular therapy of malignant gliomas. The hypotheses to be tested are; 1) Gene regulation and overexpression of MMP-9 correlate with malignant progression of human gliomas; 2) Modulation of the expression of MMP-9 (with antisense strategy) will provide an inhibitory effect on the invasive behavior of glioblastomas. The specific Aims are: 1) Determine the invasive capacity of human glioma cell lines in vivo (using nude mice) in relation to 92-kDa type IV collagenase (MMP-9); 2) Determine whether MMP-9 overexpression in cultured glioblastoma cell lines is a consequence of more stable transcript, or elevated gene promoter activity; 3) Determine the effect of an antisense MMP-9 expression vector on the invasive phenotype of cultured glioblastoma cell lines in vitro and in vivo. We believe that determination of the molecular mechanisms that underscore the overexpression of MMP-9 could lead to the development of novel anti-invasive therapeutic agents whose mode of action depends on antagonism of MMP-9 overexpression.